Immune responses to infections occur in two phases, an early relatively nonspecitic (innate) response and a later specific (adaptive or acquired).response associated with the expansions of antigen-reactive clones of T and B cells. My laboratory in the 1970s helped develop this paradigm by demonstrating an interferon (IFN)- induced activated natural killer (NK) cell peak followed by a virus-specific cytotoxic T cell peak. NK cells are now considered important anti-viral components of the innate immune system. Paradoxically, we now have surprising evidence that the depletion of NK cells can sometimes enhance viral clearance or inhibit immunopathological disease. Under these conditions NK cells are harmful to host because they alter the acquired immune response, in part by killing activated CD4 T cells, which regulate viral infections directly and indirectly by their actions on CDS T cells and B cells. However, under other conditions the presence of NK cells is needed to promote persistent infections, also in part due to their ability to regulate T cell responses. We show here that whereas the inhibitory molecule 2B4 restrains NK cells from attacking CDS T cells, activated NK cells can kill activated CD4 T cells and in so doing decrease both CD4 and CDS T cell numbers and functionality during viral infections. We propose to determine, using several different systems, the mechanism(s) by which NK cells affect newly developing T cell responses and contribute to the pathogenesis of viral disease in the lung, and we will collaborate with, other program investigators to translate these findings into human systems. Specifically, we propose the following specific aims: Specific Aim #1: To determine whether the direct NK cell control of T cell responses is a universal feature in anti-viral T cell responses. Specific Aim #2: To determine, in collaboration with Project 2 and Core 0, the functional, physiological, and antigenic state of 004 T cells that are susceptible to NK cell mediated lysis. Specific Aim #3: To determine the role of NK cells in regulating antiviral antibody responses. Specific Aim #4: To examine the NK cell-dependent regulation of pathology and persistence and effects of NK cells on T cell exhaustion. The work meets the objectives of RFA-AI-12-048, in that it (1) examines interactions between innate and adaptive immune mechanisms in viral systems, (2) examines such actions at mucosal sites, in this case the lung, and (3) examines how different T and B cell subsets are maintained after infection.